To provide a medicinal preparation of a medicinal substance which is only sparingly soluble in water (hereinafter referred to briefly as an insoluble drug), particularly such a preparation for oral administration, it is common practice to prepare a solid dispersion by mix-crystallizing a polymer such as hydroxypropylmethyl cellulose and the drug. By way of illustration, such a solid dispersion has been provided for the following FK506 (or FR-900506) Substance which, as is well known, has excellent immunosuppressant activity but is only sparingly soluble in water [Kokai Tokkyo Koho S62-277321]. ##STR1##
Generic name: tacrolimus PA1 Chemical name: 17-allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylviny l]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3. 1.0 4,9]octacos-18-ene-2,3,10,16-tetraone PA1 (a) is two adjacent hydrogen atoms, or PA1 (b) may form another bond formed between the carbon atoms to which they are attached, PA1 trisubstituted silyl group such as a tri(lower)alkylsilyl (e.g., trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyldimethylsilyl, tri-tert-butylsilyl, etc.) or lower alkyl-diarylsilyl (e.g., methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenyl-silyl, etc.), more preferably tri(C.sub.1 -C.sub.4)alkylsilyl group and C.sub.1 -C.sub.4 alkyldiphenylsilyl group, most preferably tert-butyldimethylsilyl group and tert-butyldiphenylsilyl group; and an acyl group such as an aliphatic, aromatic acyl group or an aliphatic acyl group substituted by an aromatic group, which are derived from a carboxylic acid, sulfonic acid or carbamic acid. PA1 a cyclo (lower) alkoxy (lower) alkanoyl group optionally having one or more suitable substituents such as lower alkyl, e.g., cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxypentanoyl, menthyloxyhexanoyl, etc.; a camphorsulfonyl group; or a lower alkylcarbamoyl group having one or more suitable substituents such as carboxy or protected carboxy, for example, carboxy (lower) alkylcarbamoyl group (e.g., carboxymethylcarbamoyl, carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypentylcarbamoyl, carboxyhexylcarbamoyl, etc.), tri-(lower) alkylsilyl (lower) alkoxycarbonyl (lower) alk ylcarbamoyl group (e.g., trimethylsilylmethoxycarbonylethylcarbamoyl, trimethylsilylethoxycarbonylpropylcarbamoyl, triethylsilylethoxycarbonylpropylcarbamoyl, tert-butyldimethylsilylethoxycarbonylpropylcarbamoyl, tri-methylsilylpropoxycarbonylbutylcarbamoyl, etc.) and so on. PA1 each of R.sup.8 and R.sup.23 is independently a hydrogen atom; PA1 R.sup.9 is a hydroxy group; PA1 R.sup.10 is a methyl group, an ethyl group, a propyl group or an allyl group; PA1 X is (a hydrogen atom and a hydrogen atom) or an oxo group; PA1 Y is an oxo group; PA1 each of R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18, R.sup.19, and R.sup.22 is a methyl group; PA1 each of R.sup.20 and R.sup.21 is independently (R.sup.20 a and a hydrogen atom) or (R.sup.21 a and a hydrogen atom) in which each of R.sup.20 a and R.sup.21 a is a hydroxy group or an alkoxy group, or R.sup.21 a is a protected hydroxy group; and PA1 n is an integer of 1 or 2. FK506 is the most preferable compound belonging to the tricyclic compound (I). PA1 1,14-Dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-23,25-d imethoxy-13,17,19,21,27-pentamethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup. 4,9 ]octacos-18-ene-2,3,10,16-tetraone, PA1 12-[2-(4-acetoxy-3-methoxycyclohexyl)-1-methylvinyl]-17-allyl-1,14-dihydrox y-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3. 1.0.sup.4,9 ]octacos-18-ene-2,3,10,16-tetraone, PA1 17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-12-[2-[4-(3 ,5-dinitrobenzoyloxy)-3-methoxycyclo-hexyl]-1-methylvinyl]-11,28-dioxa-4-az atricyclo[22.3.1.0.sup.4,9 ]-octacos-18-ene-2,3,10,16-tetraone, PA1 17-allyl-12-[2-[4-[(-)-2-trifluoromethyl-2-methoxy-2-phenylacetoxy]-3-metho xycyclohexyl]-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tet ramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.sup.4,9 ]octacos-18-ene-2,3,10,16-tetraone. PA1 17-ethyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclo-hexyl)-1-methylviny l]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3. 1.0.sup.4,9 ]octacos-18-ene-2,3,10,16-tetraone (FR900520), and PA1 17-ethyl-1,14,20-trihydroxy-12-[2-(3,4-dihydroxycyclo-hexyl)-1-methylvinyl] -23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3. 1.0.sup.4,9 ]octacos-18-ene-2,3,10,16-tetraone. PA1 [propylene glycolmonocaprylate (e.g. Sefsol.TM.-218), propylene glycol dicaprylate (e.g. Sefsol.TM.-228), propylene glycol monocaprate, propylene glycol dicaprate (e.g. Sefsol.TM.-220), propylene glycol monolaurate, propylene glycol monoisooctanoate (e.g. Sefsol.TM.-2126), propylene glycol diisooctanoate (e.g. Sefsol.TM.-2226), Migyol.TM. 840, etc.] PA1 [oleic acid, linoleic acid, etc.] PA1 [isopropyl myristate, butyl myristate, isocetyl myristate, octyldodecyl myristate, isopropyl palmitate, isostearyl palmitate, isopropyl isostearate, isocetyl isostearate, butyl stearate, isocetyl stearate, cetyl isooctanoate, ethyl linoleate, isopropyl linoleate, hexyl laurate, ethyl oleate, decyl oleate, oleyl oleate, octyldodecyl myristate, hexyldecyl dimethyloctanoate, octyldodecyl neodecanoate, etc.] PA1 [ethylene glycol mnonocaprylate (e.g. Sefsol.TM.-118), ethylene glycol dicaprylate (e.g. Sefsol.TM.128), ethylene glycol monoisooctanoate (e.g. Sefsol.TM.-1126), ethylene glycol diisooctanoate (e.g. Sefsol.TM.-1226), etc.] PA1 [tetraglycerin monocaprylate (e.g. Sefsol.TM.-618), tetraglycerin hexacaprylate (e.g. Sefsol.TM.-668), etc.] PA1 [diisopropyl adipate, diisobutyl adipate, diethyl sebacate, diisopropyl sebacate, diethyl phthalate, etc.] PA1 [oleyl alcohol, cetanol, stearyl alcohol, etc.] PA1 [polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene lauryl ether (lauromacrogol J.P.), etc.] PA1 [Tween.TM. 20, Tween.TM. 40, Tween.TM. 60, Tween.TM. 65, Tween.TM. 80, etc.] PA1 [polyoxyethylene glycerin monostearate etc.] PA1 [polyoxyethylene propylene glycol monostearate, polyoxyethylene propylene glycol monooleate, etc.] PA1 [polyoxyethylene sorbitol tetraoleate, polyoxyethylene sorbitol hexastearate, polyoxyethylene sorbitol monolaurate, polyoxyethylene sorbitol beeswax, etc.] PA1 [polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil (trademarks: HCO-40, HCO-60, Cremophore RH40, Cremophore RH60, etc.), polyoxyethylene lanolin, etc.] PA1 [polyethylene glycol monooleate, polyethylene glycol monostearate (e.g. polyoxyl stearate 40, J.P.), polyethylene glycol monolaurate, etc.] PA1 [sorbitan monooleate (e.g. Span.TM. 80), sorbitan monostearate (e.g. Span.TM. 60), sorbitan monopalmitate (e.g. Span.TM. 40), sorbitan monolaurate (e.g. Span.TM. 20), sorbitan monocaprylate (e.g. Sefsol.TM.-418), etc.] PA1 [DK-SS, DK-F160, DK-F140, DK-F110 (TM owned by Daiichi Kogyo Seiyaku), etc.] PA1 [Pluronic.TM. F87, Pluronic.TM. F127, Pluronic.TM. F68, Pluronic.TM. L44, Pluronic.TM. P123, Pluronic.TM. P85, Poloxamer.TM. 188, Poloxamer.TM. 235, Poloxamer.TM. 403, Poloxamer.TM. 407, etc.] PA1 [sodium lauryl sulfate etc.] PA1 [purified egg yolk lecithin, purified soybean lecithin, etc.] PA1 [sodium taurocholate, sodium glycocholate, etc.]
However, it is generally acknowledged that the oral absorbability of solid dispersions such as the above tends to vary rather appreciably.
After intensive investigations, the inventors of this invention have created a medicinal composition which, even when its active ingredient is an only sparingly water-soluble medicinal substance (insoluble drug), shows a very satisfactory drug release profile plus high oral absorption efficiency and absorbability with little variation.